Department of Pediatrics, Children's Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Hangzhou, Zhejiang Province, People's Republic of China.
Department of Pediatrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
Respir Res. 2024 Sep 2;25(1):328. doi: 10.1186/s12931-024-02957-1.
The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive.
To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats.
Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.
子宫内和早期产后环境的相互作用与成年后心血管疾病的风险增加有关，包括肺动脉高压（PAH）。虽然新出现的证据强调了线粒体病理学在 PAH 中的关键作用，但导致胎儿起源性 PAH 的具体机制仍不清楚。
为了阐明线粒体动力学在胎儿起源性 PAH 发病机制中的作用，我们建立了宫内生长受限（IUGR）后追赶生长诱导肺动脉高压（PAH）的大鼠模型。来自大鼠肺动脉样本的 RNA-seq 分析显示，与 RC 组（IUGR 后的追赶生长）中肺动脉压力升高和肺血管重塑相关的线粒体代谢基因和途径发生失调。来自 RC 组的肺动脉平滑肌细胞（PASMCs）的体外实验显示增殖、迁移增加和线粒体功能受损。值得注意的是，RC 组中观察到参与线粒体融合的线粒体外膜蛋白 Mitofusion 2（Mfn2）表达降低。在 RC 组的 PASMCs 中重建 Mfn2 导致线粒体融合增强和线粒体功能改善，有效地逆转了瓦伯格效应。重要的是，Mfn2 的重建减轻了 RC 组大鼠的 PAH 表型。
不平衡的线粒体动力学，表现为 Mfn2 表达降低，在 IUGR 后追赶生长引起的胎儿起源性 PAH 发展中起关键作用。Mfn2 作为一种有前途的治疗策略，可用于管理 IUGR 追赶生长引起的 PAH。
